Methylation in positions 1 and 7 of angiotensin II A structure-activity relationship study

Six analogues of angiotensin II (Ang) were synthesized with modifications in positions 1 and 7. The study was undertaken in order to learn more about the influence of alkylations in positions 1 and 7 and their interdependence. Previous studies have shown that x,x-dimethylation of Gly (aminoisobutyric acid, Aib) in position 1 produces quite potent analogues, as does N-methylation of Gly (sarcosine). Combination of both C^x- and N^x-methylations to N-Me-Aib¹, however, did not produce an affinity increase. Decyclisation of the Pro⁷-residue produced moderately active analogues with position 7 N-methylation and inactive analogues if the N-alkylation was suppressed. In order to investigate a possible stereochemical interdependence of positions 1 and 7, a group of peptides with combinations of position 1 and 7 alkylations were investigated. The following analogues were prepared: Sar¹, Aib⁷]Ang, Sar¹,Aib⁷,Leu⁸]Ang, Aib^1,7]Ang, Aib^1,7, Leu⁸]Ang, N-Me-Aib¹,Aib⁷]Ang, N-Me-Aib¹,Aib⁷,Leu⁸]Ang. They were synthesized by classical solid phase synthesis using the BOC-TFA-HF scheme. The biological properties of these peptides were assessed on the rabbit aorta preparation and their binding potencies were measured on bovine adrenal membranes. Both on agonistic and antagonistic Leu⁸]Ang analogues single Aib substitutions in position 1 or 7 induced affinity reduction in both bioassays. Simultaneous Aib modifications in positions 1 and 7 induced more important affinity loss in a synergic manner in both bioassays and as well for agonists and antagonists. The N-Me-Aib¹ modifications induce similar affinity loss with or without concomitant Aib⁷ modification. Agonistic (Phe⁸) analogues containing Aib in position 7 all have reduced intrinsic activity, indicating for the first time an influence of this position on the activation mechanism of the Ang receptor of the Type AT₁. © Munksgaard 1994.